Acute chest syndrome (ACS), a devastating complication of sickle cell disease (SCD), is the most common cause of disease-related mortality. Nonetheless, little is known about its pathophysiology, it is diagnosed and treated only after the disease process is well underway. Work from our laboratory suggests a novel insight into the underlying pathophysiology of ACS. We show that an erythroid-cell derived angiogenic growth factor, placental growth factor (PIGF) promotes a strong inflammatory response in SCD: it increases expression of VEGF, IL-1beta, IL-8, MCP-1, TNF alpha and tissue factor (TF) from monocytes via binding to VEGFR1/Flt-1. PIGF levels are increased in SCD plasma and correlate with disease severity. PIGF is inducible by hypoxia and erythropoietin (Epo), factors elevated in SCD. PIGF was recently found to strongly predict a) death or nonfatal myocardial infarction in patients presenting with chest pain and b) development and severity of bronchopulmonary dysplasia in newborns. We show that PIGF initiates downstream signaling events resulting in activation of early growth response-1 (Egr-1). Downstream targets of Egr-1 include VEGF, IL-1beta, MCP-1, TNFalpha, TF and 5-lipoxygenase (5LO), all of which increase leukocyte chemotaxis and inflammation; 5LO initiates the cascade that produces leukotrienes (LT). We show that SCD patients have evidence of reactive airway disease at baseline; PIGF increases expression of 5LO and 5LO activator protein from human pulmonary endothelial cells; and that PIGF-/- mice have a reduced inflammatory response to acute lung injury. ACS often follows an acute event, associated with a drop in hemoglobin. The latter would increase hypoxia, Epo and erythropoiesis, all of which increase PIGF production. We hypothesize that elevated PIGF, via its effect on inflammatory cytochemokines and leukotrienes results in increased inflammation and reactive airway disease at baseline in patients with SCD. Further elevations in PIGF levels during acute sickle events amplify the inflammation and reactive airway disease and contribute significantly to the cascade of events that result in ACS. Aim1: Knock out the PIGF gene in transgenic sickle mice and study their disease severity and response to acute lung injury. Aim 2: Determine whether elevated PIGF levels will predict ACS in SCD patients hospitalized for an acute event and that PLGF levels and LT levels will predict the magnitude of airway reactivity and obstructive lung disease in patients with SCD. Together, these aims are a focused approach combining basic science and clinical investigation to elucidate a mechanism that likely contributes to ACS, in order to enable early intervention in patients at high risk for ACS and target therapy at the underlying disease process. VEGFR-antagonists are in clinical trials and leukotriene blockers are FDA approved and in clinical use for asthma and could be candidates for an ACS prevention trial.